Several studies were designed to investigate strategies to improve endothelial dysfunction in patients with atherosclerosis and its risk factors. 1) Angiotensin converting enzyme (ACE) inhibition with enalaprilat acutely improved endothelium-dependent vasodilation in the coronary and peripheral vasculature of patients with atherosclerosis and its risk factors. This improvement was due to increased nitric oxide (NO) bioavailability with ACE inhibitors. The ACE genotype influenced the magnitude of improvement in endothelial function with ACE inhibition, with the effect being greater in patients with the D genotype.2)We examined whether angiotensin II receptor blockade with losartan improves endothelial dysfunction both acutely and after chronic oral therapy in the peripheral circulation and whether it influences coronary vascular reactivity. Results demionstrated that AT1 receptor blockade improved femoral microvascular endothelium-dependent but not -independent dilation and improved the reactive hyperemic response. Chronic therapy improved brachial artery flow-mediated vasodilation but did not change circulating levels of adhesion molecules or PAI-1 levels.3) We are currently examining whether the nitric oxide donor, sildenafil, that improves the bioavailability of cyclic GMP will a) improve coronary or periphearl artery endothelial dysfunction, and whether this has anti-anginal properties. 4) We are also investigating whether the coronary and peripheral vascular endothelial function that has been measured in over 300 patients is (a) predictive of future coronary events, (b) correlates with newer described risk factors of atherosclerosis that include inflammatory state (measured as adhesion molecules, CRP etc), coagulation parameters (tPA, PAI-1, fibrinogen), homocysteine, infections (chlamydia, H.simplex, Hepatitis A, CMV, H.pylori), metabolic factors (insulin resistance, endothelin etc.), coronary calcification and variety of genetic polymorphisms that are associated with increased of cardiovascular events. - Vascular Biology, endothelial function, Angiotensin, Sildenafil, risk factors, atherosclerosis - Human Subjects